Alterations of slow and fast rod ERG signals in patients with molecularly confirmed Stargardt disease type 1 (STGD1)

purpose. To investigate the slow and fast rod signals of the scotopic 15-Hz flicker ERG in patients with molecularly confirmed Stargardt disease type I (STGD1). There is evidence that these slow and the fast rod ERG signals can be attributed to the rod bipolar–AII cell pathway and the rod–cone coupling pathway, respectively. methods. Twenty-seven patients with STGD1 with mutations in both alleles of the ABCA4 gene were included. Scotopic ERG response amplitudes and phases to flicker intensities ranging from −3.37 to −0.57 log scotopic troland · sec (log scot td · sec) were measured at a flicker frequency of 15 Hz. In addition, scotopic standard ERGs were obtained. Twenty-two normal subjects served as controls. results. The amplitudes of both the slow and fast rod ERG signals were significantly reduced in the STGD1 group. The phases of the slow rod signals lagged significantly, whereas those of the fast rod signals did not. The standard scotopic ERG did not reveal significant alterations. conclusions. The results provide evidence that a defective ABCA4 transporter can functionally affect both the rod bipolar–AII cell pathway and the rod–cone coupling pathway. In STGD1, the scotopic 15-Hz flicker ERG may reveal subtle abnormalities at different sites within the rod system that remain undetected by standard ERG techniques

Clinical electrophysiology of two rod pathways: normative values and clinical application

Background: The scotopic 15-Hz flicker electroretinogram (ERG) has two limbs (slow and fast ERG rod signals), and these have been attributed to two retinal rod pathways (the ON rod bipolar and AII amacrine pathway and the rod-cone gap-junction pathway). The aim of this study was to provide normative values of the scotopic 15-Hz flicker ERG, to estimate the inter-individual variability, and to apply this method to a clinical setting. Methods: Twenty-two normal subjects, one patient with retinitis pigmentosa (RP), and two patients with Stargardt's macular dystrophy (SMD) participated in the study. The SMD patients were screened for mutations in the 50 exons of the ABCA4 (formerly ABCR) gene. We measured ERG response amplitudes and phases to flicker intensities ranging from –3.37 to –0.57 log scotopic trolands s at a flicker frequency of 15 Hz. Results: The normal scotopic 15-Hz flicker ERG showed a biphasic amplitude pattern with a minimum at about –1.57 log scotopic trolands s, where there was an abrupt phase shift of about 180 deg. The inter-individual variability in ERG amplitude ranged from 47% to 67% for the slow and from 41% to 64% for the fast rod signal. Both the RP patient and the SMD patients (who were compound heterozygotes for mutations in the ABCA4 gene) showed reduced amplitudes for the two rod ERG pathways. Conclusion: The inter-individual variability might be explained by anatomical differences between individual retinae. In the RP patient, the amplitude reductions corresponded well with the standard rod ERG. In the SMD patients, however, the scotopic 15-Hz flicker ERG revealed rod dysfunction, whereas the standard rod ERG was within normal limits. The scotopic 15-Hz flicker method may be more sensitive than the standard rod ERG

A second independent Tyr168Cys mutation in the tissue inhibitor of metalloproteinases-3 (TIMP3) in Sorsby's fundus dystrophy.

Sorsby's fundus dystrophy (SFD) is a rare autosomal dominant macular disorder with age of onset usually in the fourth decade. It is characterised by loss of central vision owing to subretinal neovascularisation and disciform macular degeneration. In an effort to identify the SFD gene, the disease locus was first mapped to chromosome 22q13-qter by genetic linkage analysis, the same chromosomal region as the gene encoding the tissue inhibitor of metalloproteinases-3 (TIMP3). Subsequently, two separate mutations in TIMP3 were found in affected members of two unrelated SFD pedigrees (Tyr168Cys and Ser181Cys). More recently, two additional SFD related mutations, Ser156Cys and Gly167Cys, have provided further confirmation that heterozygous mutations in TIMP3 are causally responsible for the SFD phenotype. We now report the occurrence of the Tyr168Cys mutation in an SFD patient of Austrian descent and show that this mutation found earlier in an American SFD family arose independently. The new findings add to an emerging pattern of SFD mutations which all seem to affect the C-terminal region of the mature TIMP3 protein. In addition, all known mutations cause a change of an amino acid to a cysteine residue. This suggests a critical role for the additional C-terminal free thiol group in SFD pathogenesis

Magnetic properties of the high-T_c superconductor La_1.85Sr_0.15CuO₄

For the high-T c superconductor La1.85Sr0.15CuO4, we present results for the low-field magnetization and the lower and upper critical fieldsB c1 (T) andB c2(T). ForB c1 (0) we find a value of about 20 mT. Extrapolating our resistive data for the transition midpoint taken in fields up to 12 T, we deduce a value of about 50 T forB c2 (0). TheB c2 values obtained by inductive measurements are significantly lower. We explain this by a largeB c2 anisotropy due to the layered structure of these compounds. Losses in the Meissner state observed in magnetization and susceptibility measurements disappear after powdering the sample. This is taken as strong evidence for intergrain Josephson coupling in the bulk sample

Magnetic Properties of the High-T_c Superconductors La_1.85Sr_0.15CuO₄ and YBa₂Cu₃O₇

For the high-Tc superconductors La1.85Sr0.15CuO4 and YBa2Cu3O7 we present results for the low-field magnetization and the lower and upper critical fields Bc1(T) and Bc2(T). Losses in the Meissner state observed in magnetization and susceptibility measurements disappeared after powdering the sample. This is taken as strong evidence for intergrain Josephson coupling in the bulk sample. The Bc2(T) obtained by inductive measurements indicates a large anisotropy due to the layered structure of these compounds

Molecular basis of an inherited form of incomplete achromatopsia

Mutations in the genes encoding the CNGA3 and CNGB3 subunits of the cyclic nucleotide-gated (CNG) channel of cone photoreceptors have been associated with autosomal recessive achromatopsia. Here we analyze the molecular basis of achromatopsia in two siblings with residual cone function. Psychophysical and electroretinographic analyses show that the light sensitivity of the cone system is lowered, and the signal transfer from cones to secondary neurons is perturbed. Both siblings carry two mutant CNGA3 alleles that give rise to channel subunits with different single-amino acid substitutions. Heterologous expression revealed that only one mutant forms functional channels, albeit with grossly altered properties, including changes in Ca2+ blockage and permeation. Surprisingly, coexpression of this mutant subunit with CNGB3 rescues the channel phenotype, except for the Ca2+ interaction. We argue that these alterations are responsible for the perturbations in light sensitivity and synaptic transmission

A Comprehensive Survey of Sequence Variation in the ABCA4 (ABCR) Gene in Stargardt Disease and Age-Related Macular Degeneration

Stargardt disease (STGD) is a common autosomal recessive maculopathy of early and young-adult onset and is caused by alterations in the gene encoding the photoreceptor-specific ATP-binding cassette (ABC) transporter (ABCA4). We have studied 144 patients with STGD and 220 unaffected individuals ascertained from the German population, to complete a comprehensive, population-specific survey of the sequence variation in the ABCA4 gene. In addition, we have assessed the proposed role for ABCA4 in age-related macular degeneration (AMD), a common cause of late-onset blindness, by studying 200 affected individuals with late-stage disease. Using a screening strategy based primarily on denaturing gradient gel electrophoresis, we have identified in the three study groups a total of 127 unique alterations, of which 90 have not been previously reported, and have classified 72 as probable pathogenic mutations. Of the 288 STGD chromosomes studied, mutations were identified in 166, resulting in a detection rate of ∼58%. Eight different alleles account for 61% of the identified disease alleles, and at least one of these, the L541P-A1038V complex allele, appears to be a founder mutation in the German population. When the group with AMD and the control group were analyzed with the same methodology, 18 patients with AMD and 12 controls were found to harbor possible disease-associated alterations. This represents no significant difference between the two groups; however, for detection of modest effects of rare alleles in complex diseases, the analysis of larger cohorts of patients may be required